The present invention is directed to compositions useful in alleviating the symptoms of mammalian respiratory distress syndrome (RDS) which may occur in the newborn, and especially in the prematurely newborn, as well as, in many instances in the adult when disease or functional difficulties bring about lung failure characterized by the deficiency of lung surfactant. The invention compositions may be introduced into the lungs of the distressed subject to temporarily provide the surfactant required for proper pulmonary function.
In the past several decades, the findings and writings of a number of investigators have brought greatly increased understanding in the medical community of the physiology of the mammalian lung; especially pertaining to the mechanisms involved in the transfer of gases from the air spaces in the lungs across the lining tissues to the underlying vascular system. These studies have revealed the critical role played by a liquid film which lines the tissue surfaces. This role is based upon basic physical principles which have been known for several hundred years, but whose application to the operation of the mammalian lung has only reached general recognition within the past 20 years or so.
Specifically, the basic physics principles involve the functioning of surface tension, i.e., the physical phenomenon exhibited by liquid surfaces brought about by intermolecular forces and resulting in a "skin like" effect. This phenomenon underlies the tendency of the lung's air sacs, or alveoli, to expell gas at all times during the respiratory cycle. If sufficiently low surface tension forces are not maintained at the air-lung tissue interface, the alveoli collapse during exhalation. Even the inspiration of air through the bronchi may be ineffective in inflating the collapsed alveoli and gas exchange into the pulmonary circulatory system may be inadequate.
Establishing and maintaining low surface tension at the alveolar surfaces is accomplished by an intricate biological system associated with alveolar lung tissue. Special cells, known as alveolar Type II, synthesize a complex mixture of lipids, proteins, glycerides and fatty acids. This complex is stored in the form of lamellar bodies within the alveolar Type II cells. By a mechanism little understood, the lamellar bodies are extruded from the alveolar Type II cells into alveolar lumen where the lamellae unwind and distribute the lipid, protein, glyceride, etc. molecules throughout the liquid film which bathes the entire cellular covering of the alveolar walls. These molecules, which may be generically referred to as "lung surfactant," migrate to the surface of the liquid film where they produce an essentially mono-molecular, all pervasive layer thereon.
The surfactant, effectively lowers the surface tension of the film to low values (circa 10 millineutons/meter) sufficient to maintain alveolar inflation during all phases of the respiratory cycle.
The chemical composition of "lung surfactant" has been investigated and the results have been published in a number of papers, e.g. Respiratory Distress Syndrome, Academic Press Inc., 1973, pp. 77-98. Such studies indicate that natural lung surfactant is a complex mixture of many components of which the major component is a lipid, dipalmitoyl phosphatidyl choline (according to current naming criteria more correctly, 1,2-dipalmitoyl-sn-3-glycerophosphoryl choline). Dipalmitoyl phosphatidyl choline, commonly abbreviated as DPPC, occurs in lung surfactant to the extent of about 41% by weight. Mixed monenoic lecithins make up about 25% by weight; cholesterol makes up about 9% by weight; mixed proteins about 9% by weight; phosphatidyl ethanolamine, about 5%; various glycerides and phosphatidyl serine and phosphatidyl glycerol, about 4%, respectively; lysolecithin, about 2%; with sphingomyelin and fatty acids, each about 1%. The above noted materials and %'s are for surfactant removed from canine lungs; however, the mix of materials and %'s generally hold true for the higher mammals. For instance, both bovine and human lung surfactant also comprise a similar mix, with DPPC running in the same range of approximately 40% by weight.
Respiratory distress syndrome occurs when the necessary surfactant is either absent from, or is seriously depleted in, the liquid lining of the alveolar spaces. The most common occurrance is in the newborn and especially in the premature newborn, wherein development of the alveolar Type II cells has not yet arrived at a stage sufficient to generate the necessary surfactant material. The maturation of the alveolar Type II cells normally occurs within the last several weeks of full term gestation. However, in some instances congenital defects interfere with and/or delay maturation of the alveolar Type II cells; or more commonly in the instance of premature birth, maturation has not yet progressed sufficiently to generate the necessary surfactant.
In other instances, interruption of the generation of surfactant may occur in the mature and/or adult individual under the impact of disease and/or trauma.
It will be apparent from what has been noted herein and before that the lack of maturation of the surfactant generating mechanisms in the newborn and especially in the prematurely newborn, or the interruption of the surfactant generating mechanism resulting from disease or trauma, will result in the absence or the diminution of the necessary surfactant on the lining of the alveolar spaces. The absence of the necessary surfactant eliminates or may drastically interfer with the ability of the newborn lung to properly inflate as respiration begins. Similarly, collapse or deflation of the alveolar spaces occurs in the mature lung when the supply of surfactant is interrupted or diminished because of disease or trauma.
The absence or loss of lung surfactant is manifest by severe respiratory distress, which if not managed by medical intervention may most usually result in death. In the past, such medical intervention included such measures as supplying high levels of oxygen; positive pressure application to the lungs to provide adequate pulmonary ventilation; adequate attention to the maintenance of nutrition, fluid balance, blood volume, and blood pressure etc. In addition, in the case of the premature newborn it has been determined that the introduction of corticosteroids actively induces rapid maturation of the natural surfactant production system. Such steroid therapy, however, must be undertaken before the actual premature birth occurs in order to be truly effective in achieving early maturation of the surfactant producing systems. With recent techniques of analyzing amniotic fluids, tests have been devised for determining the presence of adequate amounts of surfactant in the unborn fetus. Where it is anticipated that a premature birth will occur, such tests can be performed and if inadequate levels of surfactant are noted, steroid therapy can be instituted to hasten the maturation of the natural surfactant production systems.
Rather fortuitously soon after birth the corticosteroid systems begin and/or increase production of the corticosteroids internally and if the individual can be maintained for relatively short periods of time, in the matter of several days, maturation of the surfactant production systems will occur. Under these circumstances sufficient surfactants will soon be released into the alveolar surfaces to produce the low surface tension necessary to the full and unassisted expansion to maintain normal respiratory function.
Therefore, it becomes extremely critical to somehow manage the respiratory distress for a relatively short period of time (normally for a period of several days) until the natural systems can come into play and take over their role in maintaining a normal expansion of the alveolar spaces.
As pointed out above, in the past, management has included positive pressure pulmonary ventilation along with the monitoring and maintenance of secondary functions. However, with the discovery of the nature of lung surfactant, some work has been done to replace the lacking surfactant with exogenous surfactant components. Generally speaking, however, such attempts have been unsuccessful until Fujiwara and his coworkers used cow lung extract fortified with DPPC and phosphatidylglycerol, two of the principal components of natural lung surfactant. Fujiwara, et al. reported their work in Lancet 1:55, January 1980.
One of the possible shortcomings of a substitute surfactant derived from animal lung extracts are its undefined nature, the possibility of contamination with micro-organisms, and especially the presence of foreign proteins which may lead to possible sensitization in the individual to whom such extracts are administered. It is therefore desirable to develop a lung surfactant substitute whose composition is completely defined, whose production may essentially exclude any possibility of microbial contamination, and in which, antigenic proteins are completely absent.
With regard to the preparation of artificial lung surfactant compositions which are free of protein, I. L. Metcalfe and his coworkers have reported (J. Applied Physiology: Respiratory Environmental Exercise Physiology 49:34, 1980) that a composition of 70% DPPC, 20% egg phosphatidylcholine, 10% phosphotidylinositol and 1% palmitic acid, exhibits acceptable properties. Similarly, C. J. Morley at the 16th International Congress of Pediatrics held at Barcelona, September 1980 reported that an artificial surfactant consisting of DPPC and unsaturated phosphatidylglycerol shows promise.
Despite the reports of synthetic surfactant noted above, the preparation of a protein free synthetic lung surfactant substitute suitable as a temporary replacement for natural lung surfactant has been quite difficult since the physiochemical characteristics of natural lung surfactant are complex and at times contradictory. The principal characteristics of a lung surfactant are (1) it must absorb very rapidly from bulk phase to the liquid interface lining the alveolar tissues and spread a film thereon. The film must be formed rapidly since newborns have a high respiratory rate and only a few tenths of a second is available during inspiration to form the film while the air spaces are expanding. (2) The surfactant surface film must be stable to ensure that the surface tension remains at a low value (not more than 10 mN/m) during expiration. The stable film ensures that as transpulmonary pressure falls, the alveolar spaces remain expanded and functional; and that residual volume does not decrease to zero. (3) Although some of the surfactant material inevitably is forced from the interfacial film during expiration, it is essential that the surfactant have sufficient mobility to reenter the interface during the next expansion. Such properties of the surfactant ensures that its loss from the interfacial film is not so high as to require excessive dosage volumes and/or rates.
Some of the requirements for the surfactants as noted above, appear to be contradictory insofar as the physicochemical properties of the lung surfactant materials are concerned. Thus, the high molecular mobility required for rapid adsorption and respreading into the interfacial film contradicts the low mobility necessary for a stable and persistent film. In natural lung surfactant, this contradiction is apparently resolved through the complexity of the multicomponents as noted above which are organized around a specific protein. Such complex material apparently has the ability to spontaneously undergo the necessary molecular sorting and phase changes required to satisfy these apparently contradictory physico chemical requirements. Thus the preparation of a simple, yet effective synthetic lung surfactant appears to be fought with difficulty.